The broad, long term goals of this project are to discover multiple new lead compounds that are candidates for the treatment of malaria and to push these compounds as far forward as possible through preclinical studies. The health relatedness of these goals lies in the fact that there are few available drugs to treat malaria and many of those that are available are subject to clinical resistance. In fact, resistance to available drugs has been identified as the primary difficulty in the treatment of malaria. Co-therapy has emerged as the best practical solution to this problem. Therefore, the basic logical assumption of this proposal is that the development of multiple drug candidates will enable the suppression of the development of clinical resistance. This program targets two relatively unaddressed target classes: cation channels and kinases. As a back up strategy, the program also targets compounds with the same mechanism of action as existing quinolines. The research design and methods for achieving these goals involves the use of parallel medicinal chemistry;in vitro and in vivo measures of compound efficacy;and in vitro and in vivo measures of compound availability, distribution, metabolism, excretion, and toxicity. Compounds will be incrementally improved by applying cycles of these methods and refining the model that defines the overall best balance of these traits in a molecule between cycles. Compound series that fail to progress will be abandoned and progression monitored using a milestone driven model with a defined decision matrix for compound progression. The specific aims of this program are: 1. Develop five lead series (LO) with divergent chemotypes and presumptive mechanisms of action 2. Simultaneously optimize efficacy against drug resistant P. falciparum in vitro and favorable in vitro cellular and biochemical pharmacological profiles for each series 3. Optimize up to five promising validated lead series (L1, L2) using in vivo rodent efficacy, pharmacokinetic, and toxicology models 4. Optimize up to three promising late stage lead series (L3) using in vivo simian efficacy, pharmacokinetic, and toxicology models 5. Select two preclinical candidates (PO) from these series